Biomaterials and tissue engineering in traumatic brain injury:novel perspectives on promoting neural regeneration

Traumatic brain injury is a serious medical condition that can be attributed to falls, motor vehicle accidents, sports injuries and acts of violence, causing a series of neural injuries and neuropsychiatric symptoms. However, limited accessibility to the injury sites, complicated histological and anatomical structure, intricate cellular and extracellular milieu, lack of regenerative capacity in the native cells, vast variety of damage routes, and the insufficient time available for treatment have restricted the widespread application of several therapeutic methods in cases of central nervous system injury. Tissue engineering and regenerative medicine have emerged as innovative approaches in the field of nerve regeneration. By combining biomaterials, stem cells, and growth factors, these approaches have provided a platform for developing effective treatments for neural injuries, which can offer the potential to restore neural function, improve patient outcomes, and reduce the need for drugs and invasive surgical procedures. Biomaterials have shown advantages in promoting neural development, inhibiting glial scar formation, and providing a suitable biomimetic neural microenvironment, which makes their application promising in the field of neural regeneration. For instance, bioactive scaffolds loaded with stem cells can provide a biocompatible and biodegradable milieu. Furthermore, stem cells-derived exosomes combine the advantages of stem cells, avoid the risk of immune rejection, cooperate with biomaterials to enhance their biological functions, and exert stable functions, thereby inducing angiogenesis and neural regeneration in patients with traumatic brain injury and promoting the recovery of brain function. Unfortunately, biomaterials have shown positive effects in the laboratory, but when similar materials are used in clinical studies of human central nervous system regeneration, their efficacy is unsatisfactory. Here, we review the characteristics and properties of various bioactive materials, followed by the introduction of applications based on biochemistry and cell molecules, and discuss the emerging role of biomaterials in promoting neural regeneration. Further, we summarize the adaptive biomaterials infused with exosomes produced from stem cells and stem cells themselves for the treatment of traumatic brain injury. Finally, we present the main limitations of biomaterials for the treatment of traumatic brain injury and offer insights into their future potential.

Biomaterials and emerging technologies for tissue engineering and in vitro models

The latest advances in the field of biomaterials have opened new avenues for scientific breakthroughs in tissue engineer-ing which greatly contributed for the successful translation of tissue engineering products into the market/clinics.Bio-materials are easily processed to become similar to natural extracellular matrix,making them ideal temporary supports for mimicking the three-dimensional(3D)microenvironment required for maintaining the adequate cell/tissue functions both in vitro and in vivo^([1]).

Stiffness-tunable biomaterials provide a good extracellular matrix environment for axon growth and regeneration

Neuronal growth, extension, branching, and formation of neural networks are markedly influenced by the extracellular matrix—a complex network composed of proteins and carbohydrates secreted by cells. In addition to providing physical support for cells, the extracellular matrix also conveys critical mechanical stiffness cues. During the development of the nervous system, extracellular matrix stiffness plays a central role in guiding neuronal growth, particularly in the context of axonal extension, which is crucial for the formation of neural networks. In neural tissue engineering, manipulation of biomaterial stiffness is a promising strategy to provide a permissive environment for the repair and regeneration of injured nervous tissue. Recent research has fine-tuned synthetic biomaterials to fabricate scaffolds that closely replicate the stiffness profiles observed in the nervous system. In this review, we highlight the molecular mechanisms by which extracellular matrix stiffness regulates axonal growth and regeneration. We highlight the progress made in the development of stiffness-tunable biomaterials to emulate in vivo extracellular matrix environments, with an emphasis on their application in neural repair and regeneration, along with a discussion of the current limitations and future prospects. The exploration and optimization of the stiffness-tunable biomaterials has the potential to markedly advance the development of neural tissue engineering.

Treatment of spinal cord injury with biomaterials and stem cell therapy in non-human primates and humans

Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.

Biomimetic natural biomaterials for tissue engineering and regenerative medicine:new biosynthesis methods,recent advances,and emerging applications

Biomimetic materials have emerged as attractive and competitive alternatives for tissue engineering(TE)and regenerative medicine.In contrast to conventional biomaterials or synthetic materials,biomimetic scaffolds based on natural biomaterial can offer cells a broad spectrum of biochemical and biophysical cues that mimic the in vivo extracellular matrix(ECM).Additionally,such materials have mechanical adaptability,micro-structure interconnectivity,and inherent bioactivity,making them ideal for the design of living implants for specific applications in TE and regenerative medicine.This paper provides an overview for recent progress of biomimetic natural biomaterials(BNBMs),including advances in their preparation,functionality,potential applications and future challenges.We highlight recent advances in the fabrication of BNBMs and outline general strategies for functionalizing and tailoring the BNBMs with various biological and physicochemical characteristics of native ECM.Moreover,we offer an overview of recent key advances in the functionalization and applications of versatile BNBMs for TE applications.Finally,we conclude by offering our perspective on open challenges and future developments in this rapidly-evolving field.

Role of dendritic cells in MYD88-mediated immune recognition and osteoinduction initiated by the implantation of biomaterials

Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects.Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials.Previous studies have mainly focused on innate immune cells such as macrophages.In our previous work,we found that T lymphocytes,as adaptive immune cells,are also essential in the osteoinduction procedure.As the most important antigen-presenting cell,whether dendritic cells(DCs)can recognize non-antigen biomaterials and participate in osteoinduction was still unclear.In this study,we found that surgical trauma associated with materials implantation induces necrocytosis,and this causes the release of high mobility group protein-1(HMGB1),which is adsorbed on the surface of bone substitute materials.Subsequently,HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells,and the inflammatory response was activated.Finally,activated DCs release regeneration-related chemokines,recruit mesenchymal stem cells,and initiate the osteoinduction process.This study sheds light on the immune-regeneration process after bone substitute materials implantation,points out a potential direction for the development of bone substitute materials,and provides guidance for the development of clinical surgical methods.

Additive manufacturing of sustainable biomaterials for biomedical applications

Biopolymers are promising environmentally benign materials applicable in multifarious applications.They are especially favorable in implantable biomedical devices thanks to their excellent unique properties,including bioactivity,renewability,bioresorbability,biocompatibility,biodegradability and hydrophilicity.Additive manufacturing(AM)is a flexible and intricate manufacturing technology,which is widely used to fabricate biopolymer-based customized products and structures for advanced healthcare systems.Three-dimensional(3D)printing of these sustainable materials is applied in functional clinical settings including wound dressing,drug delivery systems,medical implants and tissue engineering.The present review highlights recent advancements in different types of biopolymers,such as proteins and polysaccharides,which are employed to develop different biomedical products by using extrusion,vat polymerization,laser and inkjet 3D printing techniques in addition to normal bioprinting and four-dimensional(4D)bioprinting techniques.It also incorporates the influence of nanoparticles on the biological and mechanical performances of 3D-printed tissue scaffolds,and addresses current challenges as well as future developments of environmentally friendly polymeric materials manufactured through the AMtechniques.Ideally,there is a need for more focused research on the adequate blending of these biodegradable biopolymers for achieving useful results in targeted biomedical areas.We envision that biopolymer-based 3D-printed composites have the potential to revolutionize the biomedical sector in the near future.

Osteoimmunity-regulating biomaterials promote bone regeneration

Osteoimmunomodulation is a fascinating approach for balancing osteoimmune through regulating reciprocal interactions between bone cells and immune cells[1].Implantation of the osteoimmunity-regulating biomaterials regulates osteoimmune conditions in the host dynamically,thus intensifying osseointegration under physiological microenvironments[1].This perspective presents a brief overview of osteoimmunity-regulating biomaterials for augmenting bone regeneration based on a recently published study by our research team[2].

Development of micro/nanostructured‒based biomaterials with biomedical applications

Natural biomaterials are now frequently used to build biocarrier systems,which can carry medications and biomolecules to a target region and achieve a desired therapeutic effect.Biomaterials and polymers are of great importance in the synthesis of nanomaterials.The recent studies have tended to use these materials because they are easily obtained from natural sources such as fungi,algae,bacteria,and medicinal plants.They are also biodegradable,compatible with neighborhoods,and non-toxic.Natural biomaterials and polymers are chemically changed when they are linked by cross linking agents with other polymers to create scaffolds,matrices,composites,and interpenetrating polymer networks employing microtechnology and nanotechnology.This review highlights how microengineered and nanoengineered biomaterials are utilized to produce efficient drug-delivery systems and biomedical and biological therapies and how innovative sources of biomaterials have been identified.

SYNTHETI C STUDIES ON BLOOD COMPATIBLE BIOMATERIALS Ⅳ. SYNTHESIS, CHARACTERIZATION AND ANTITHROMBOGENICITY OF POLY-[N, N'( p,p-OXYDIPHENYLENE)] PYROMELLI-TIMIDE-POLYDIMETHYLDIPHENYLSILOXANE SEGMENTED COPOLYMER

A novel class of aromatic polyimide-silicone segmented copolymer was synthesized with α, ω-bis (γ-aminopropyl) polydimethyldiphenylsiloxane (APMPS) as a silicone segment precursor, from which the segmented polyamic acid-b-silicone intermediate could be prepared simply with DMF as solvent. The segmented copolymer displays microphase separation and exhibits improved antithrombogenicity, which depends mainly upon both the content level and the DP of the silicone segment. Thermal stability and mechanical property of the copolymer are between that of the aromatic polyimide and the silicone, and also relate to both the content level and the DP of the silicone segment.

Implant biomaterials: A comprehensive review

Appropriate selection of the implant biomaterial is a key factor for long term success of implants. The biologic environment does not accept completely any material so to optimize biologic performance, implants should be selected to reduce the negative biologic response while maintaining adequate function. Every clinician should always gain a thorough knowledge about thedifferent biomaterials used for the dental implants. This article makes an effort to summarize various dental biomaterials which were used in the past and as well as the latest material used now.

Role and prospects of regenerative biomaterials in the repair of spinal cord injury

Axonal junction defects and an inhibitory environment after spinal cord injury seriously hinder the regeneration of damaged tissues and neuronal functions. At the site of spinal cord injury, regenerative biomaterials can fill cavities, deliver curative drugs, and provide adsorption sites for transplanted or host cells. Some regenerative biomaterials can also inhibit apoptosis, inflammation and glial scar formation, or further promote neurogenesis, axonal growth and angiogenesis. This review summarized a variety of biomaterial scaffolds made of natural, synthetic, and combined materials applied to spinal cord injury repair. Although these biomaterial scaffolds have shown a certain therapeutic effect in spinal cord injury repair, there are still many problems to be resolved, such as product standards and material safety and effectiveness.

Fracture Toughness Properties of Three Different Biomaterials Measured by Nanoindentation

The fracture toughness of hard biomaterials, such as nacre, bovine hoof wall and beetle cuticle, is associated with fibrous or lamellar structures that deflect or stop growing cracks. Their hardness and reduced modulus were measured by using a nanoindenter in this paper. Micro/nanoscale cracks were generated by nanoindentation using a Berkovich tip. Nanoindentation of nacre and bovine hoof wall resulted in pile-up around the indent. It was found that the fracture toughness （Kc） of bovine hoof wall is the maximum, the second is nacre, and the elytra cuticle of dung beetle is the least one.

MOLECULAR ENGINEERING STUDIES ON NONTHROMBOGENIC BIOMATERIALS——A NOVEL CLASS OF NONTHROMBOGENIC BIOMATERIALS WITH ZWITTERIONIC STRUCTURE OF CARBOXYBETAINES

N,N-dimethyl-N-methacryloyloxyethyl-N-carboxyethyl ammonium(DMMCA)was graft-copolymerized onto thesurface of segmented poly(ether urethane)(SPEU)and PE film.The carboxybetaine structure on SPEU and PE filmsurfaces was confirmed by ATR-FTIR,XPS and water contact angle measurements.Through the experiments with plateletadhesion and protein adhesion assay in vitro,the two materials studied,including poly-DMMCA gel,all show excellentnonthrombogenicity.This confirms once again that the zwitterionic molecular structure on the surfaces of materials isessential for improving their nonthrombogenicity and biocompatibility.

Review of magnesium-based biomaterials and their applications

In biomedical applications,the conventionally used metallic materials,including stainless steel,Co-based alloys and Ti alloys,often times exhibit unsatisfactory results such as stress shielding and metal ion releases.Secondary surgical operation(s)usually become inevitable to prevent long term exposure of body with the toxic implant contents.The metallic biomaterials are being revolutionized with the development of biodegradable materials including several metals,alloys,and metallic glasses.As such,the nature of metallic biomaterials are transformed from the bioinert to bioactive and multi-biofunctional(anti-bacterial,anti-proliferation,anti-cancer,etc.).Magnesium-based biomaterials are candidates to be used as new generation biodegradable metals.Magnesium(Mg)can dissolve in body fluid that means the implanted Mg can degrade during healing process,and if the degradation is controlled it would leave no debris after the completion of healing.Hence,the need for secondary surgical operation(s)for the implant removal could be eliminated.Besides its biocompatibility,the inherent mechanical properties of Mg are very similar to those of human bone.Researchers have been working on synthesis and characterization of Mg-based biomaterials with a variety of composition in order to control the degradation rate of Mg since uncontrolled degradation could result in loss of mechanical integrity,metal contamination in the body and intolerable hydrogen evolution by tissue.It was observed that the applied methods of synthesis and the choice of components affect the characteristics and performance of the Mg-based biomaterials.Researchers have synthesized many Mg-based materials through several synthesis routes and investigated their mechanical properties,biocompatibility and degradation behavior through in vitro,in vivo and in silico studies.This paper is a comprehensive review that compiles,analyses and critically discusses the recent literature on the important aspects of Mg-based biomaterials.

SYNTHETIC STUDIES ON BLOOD COMPATIBLE BIOMATERIALSⅡ. SYNTHESIS OF POLY(ETHYLENEGLYCOL MONOMETHYLLTHER ) METHACRYLATE AND ANTITHROMBOGENICITY OF ITS COPOLYMERS

Poly （ethyleneglycol monomethylether） methacrylate （PEGMM）was synthesized by means of the reaction of methacrylyl chloride with sodium monomethylpolyethyleneglycoxide and was characterized by FTIR,;H-NMR,and ultraviolet spectrometries. A series of poly （vinyl alcohol）-graft-PEGMM （PVA-g-PEGMM ）and methyl methacrylate-PEGMM copolymer （PMMA-PEGMM） were prepared and tested for antithrombogenicity in vitro. The results indicate that the antithrombogenicity of the copolymers basically increases with the increasing of the DP of polyoxyethylene （POE） chain and tends to a plateau after the DP around 114,i.e. the long chain structure of POE is favourable to the antithrombogenicityof its copolymers ;moreover, the extent of the improvement ofantithrombogenicity also relates to the PEGMM content of the copolymers and the kind of the matrix that the POE chains are located on. These results are consistent with the anticipation of the hypothesis of maintaining proteins normal conformations for blood compatible bioraaterials.

Biocompatibility evaluation in vitro. Part I: Morphology expression and proliferation of human and rat osteoblasts on the biomaterials

The biocompatibility evaluation of calcium phosphate based biomaterials is performed by tissue culture in vitro model. Three kinds of bioceramic materials which are potential to deal with bone trauma and/or conduct tissue growth are recommodated. The biological research results show that human and animal osteoblast cells anchor the materials surface in two hours in culture. Confocal laser scanning microscopy (CLSM) demonstrated the normal cell distribution and proliferation on both of dense and porous biomaterials. Hydroxyapatite and tricalcium phosphate stimulate cell proliferation. However, DNA and protein synthesis were considerably limited and the apoptosis phenomenon would be present on the hydroxyapatite (HA) materials by adding Al, Mg elements. Several important methods of biocompatibility evaluation of implant materials are described and the related biological molecular techniques such as tissue culture, cell transfection, cellular DNA stain, and Lowry assay are involved in the present research.

On the road to smart biomaterials for bone research: definitions, concepts, advances, and outlook

The demand for biomaterials that promote the repair,replacement,or restoration of hard and soft tissues continues to grow as the population ages.Traditionally,smart biomaterials have been thought as those that respond to stimuli.However,the continuous evolution of the field warrants a fresh look at the concept of smartness of biomaterials.This review presents a redefinition of the term“Smart Biomaterial”and discusses recent advances in and applications of smart biomaterials for hard tissue restoration and regeneration.To clarify the use of the term“smart biomaterials”,we propose four degrees of smartness according to the level of interaction of the biomaterials with the bio-environment and the biological/cellular responses they elicit,defining these materials as inert,active,responsive,and autonomous.Then,we present an up-to-date survey of applications of smart biomaterials for hard tissues,based on the materials’responses(external and internal stimuli)and their use as immune-modulatory biomaterials.Finally,we discuss the limitations and obstacles to the translation from basic research(bench)to clinical utilization that is required for the development of clinically relevant applications of these technologies.

Review of a new bone tumor therapy strategy based on bifunctional biomaterials

Bone tumors,especially those in osteosarcoma,usually occur in adolescents.The standard clinical treatment includes chemotherapy,surgical therapy,and radiation therapy.Unfortunately,surgical resection often fails to completely remove the tumor,which is the main cause of postoperative recurrence and metastasis,resulting in a high mortality rate.Moreover,bone tumors often invade large areas of bone,which cannot repair itself,and causes a serious effect on the quality of life of patients.Thus,bone tumor therapy and bone regeneration are challenging in the clinic.Herein,this review presents the recent developments in bifunctional biomaterials to achieve a new strategy for bone tumor therapy.The selected bifunctional materials include 3D-printed scaffolds,nano/microparticle-containing scaffolds,hydrogels,and bone-targeting nanomaterials.Numerous related studies on bifunctional biomaterials combining tumor photothermal therapy with enhanced bone regeneration were reviewed.Finally,a perspective on the future development of biomaterials for tumor therapy and bone tissue engineering is discussed.This review will provide a useful reference for bone tumor-related disease and the field of complex diseases to combine tumor therapy and tissue engineering.

Conductive Biomaterials as Bioactive Wound Dressing for Wound Healing and Skin Tissue Engineering

Conductive biomaterials based on conductive polymers,carbon nanomaterials,or conductive inorganic nanomaterials demonstrate great potential in wound healing and skin tissue engineering,owing to the similar conductivity to human skin,good antioxidant and antibacterial activities,electrically controlled drug delivery,and photothermal effect.However,a review highlights the design and application of conductive biomaterials for wound healing and skin tissue engineering is lacking.In this review,the design and fabrication methods of conductive biomaterials with various structural forms including film,nanofiber,membrane,hydrogel,sponge,foam,and acellular dermal matrix for applications in wound healing and skin tissue engineering and the corresponding mechanism in promoting the healing process were summarized.The approaches that conductive biomaterials realize their great value in healing wounds via three main strategies(electrotherapy,wound dressing,and wound assessment)were reviewed.The application of conductive biomaterials as wound dressing when facing different wounds including acute wound and chronic wound(infected wound and diabetic wound)and for wound monitoring is discussed in detail.The challenges and perspectives in designing and developing multifunctional conductive biomaterials are proposed as well.